Multiple myeloma (MM) is a devastating and incurable clonal plasma cell (PC) malignancy that is preceded by a highly prevalent asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) or a less prevalent, more advanced stage called smoldering MM (SMM). Both groups of patients have a significantly increased, life-long risk of progression to MM, however, a diagnosis of MM is not made until there are overt clinical manifestations of serious end-organ damage. As a result, MGUS and SMM patients with evolving disease do not receive treatment until they become symptomatic. Although a number of useful prognostic factors have been identified, the field still lacks an accurate and sensitive biomarker(s) that identifies MGUS and SMM patients who have begun to progress before displaying symptoms. In this regard, it has been known for over 75 years that cancer cells undergo a distinct metabolic adaptation by which glucose uptake is considerably enhanced to meet the augmented cellular demand for nucleotides, lipids, and amino acids created by increased rates of cellular proliferation accompanying tumor progression. This metabolic alteration, termed aerobic glycolysis (AG), is known to be promoted by mitochondrial defects, oncogenic signals, microenvironmental hypoxia, and abnormal expression of certain metabolic enzymes. AG also underlies the clinical utility of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the management of various tumors. The nearly universal characteristic of preferential glycolytic metabolism by cancer cells suggests this alteration provides a selective proliferative advantage and may potentially be a requisite step in tumor progression. In this regard, MM cells are known to display increased glucose uptake based on positive FDG-PET scans in these patients. Despite the FDG avidity of MM cells, the role of altered cellular metabolism as an essential factor in MGUS and SMM progression to MM remains uninvestigated. On this basis, as well as our preliminary data, we hypothesize that MGUS and SMM PC metabolic reprogramming resulting in activation of the AG pathway is the common, unifying event underlying genetically diverse MGUS and SMM progression to MM. Here, we propose that assessment of AG at the PC level will provide a novel, sensitive, and accurate means of early detection of MGUS and SMM transition to MM. Two specific aims are proposed. Aim 1 will determine the metabolic phenotype of abnormal PCs in MGUS, SMM, and MM patients, and identify key AG genes underlying this metabolic alteration. The identified AG genes will also serve as candidate biomarkers for accurately identifying MGUS and SMM patients who are progressing to MM but are still asymptomatic. Aim 2 will define the biological role of these key AG genes in MM cell proliferation. The overall impact of our study derives from the mechanistic insights that will be gained and the discovery of novel biomarkers. Furthermore, demonstration that certain AG genes are required for disease progression and/or pathogenesis would also foster development of novel targeted therapies. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) is a typically fatal plasma cell (PC) cancer that is preceded by two asymptomatic precursor conditions, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). We hypothesize that metabolic reprogramming, which causes a significant increase in glucose consumption, plays an essential role in disease progression to MM. We aim to identify the specific genetic changes that cause metabolic reprogramming thereby identifying important therapeutic targets as well as biomarkers that would identify patients with MGUS and SMM before they evolve into symptomatic MM.